| Structural highlights
Function
[HPF1_HUMAN] Acts as a cofactor for serine ADP-ribosylation by conferring serine specificity on PARP1 and PARP2: interacts with PARP1 and PARP2 and is able to change amino acid specificity toward serine (PubMed:28190768, PubMed:29480802). Promotes histone serine ADP-ribosylation in response to DNA damage, limiting DNA damage-induced PARP1 hyper-automodification, and ensuring genome stability (PubMed:27067600, PubMed:28190768). Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:29480802). HPF1 also promotes tyrosine ADP-ribosylation, probably by conferring tyrosine specificity on PARP1 (PubMed:30257210).[1] [2] [3] [4]
Publication Abstract from PubMed
The anti-cancer drug target poly(ADP-ribose) polymerase 1 (PARP1) and its close homologue, PARP2, are early responders to DNA damage in human cells(1,2). Upon binding to genomic lesions, these enzymes utilise NAD(+) to modify a plethora of proteins with mono- and poly(ADP-ribose) signals that are important for subsequent chromatin decompaction and repair factor recruitment(3,4). These post-translational modification events are predominantly serine-linked and require HPF1, an accessory factor that is specific for the DNA damage response and switches the amino-acid specificity of PARP1/2 from aspartate/glutamate to serine residues(5-10). Here, we report a co-structure of HPF1 bound to the catalytic domain of PARP2 that, in combination with NMR and biochemical data, reveals a composite active site formed by residues from both PARP1/2 and HPF1. We further show that the assembly of this new catalytic centre is essential for DNA damage-induced protein ADP-ribosylation in human cells. In response to DNA damage and NAD(+) binding site occupancy, the HPF1-PARP1/2 interaction is enhanced via allosteric networks operating within PARP1/2, providing an additional level of regulation in DNA repair induction. As HPF1 forms a joint active site with PARP1/2, our data implicate HPF1 as an important determinant of the response to clinical PARP inhibitors.
HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation.,Suskiewicz MJ, Zobel F, Ogden TEH, Fontana P, Ariza A, Yang JC, Zhu K, Bracken L, Hawthorne WJ, Ahel D, Neuhaus D, Ahel I Nature. 2020 Feb 6. pii: 10.1038/s41586-020-2013-6. doi:, 10.1038/s41586-020-2013-6. PMID:32028527[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Gibbs-Seymour I, Fontana P, Rack JGM, Ahel I. HPF1/C4orf27 Is a PARP-1-Interacting Protein that Regulates PARP-1 ADP-Ribosylation Activity. Mol Cell. 2016 May 5;62(3):432-442. doi: 10.1016/j.molcel.2016.03.008. Epub 2016 , Apr 7. PMID:27067600 doi:http://dx.doi.org/10.1016/j.molcel.2016.03.008
- ↑ Bonfiglio JJ, Fontana P, Zhang Q, Colby T, Gibbs-Seymour I, Atanassov I, Bartlett E, Zaja R, Ahel I, Matic I. Serine ADP-Ribosylation Depends on HPF1. Mol Cell. 2017 Mar 2;65(5):932-940.e6. doi: 10.1016/j.molcel.2017.01.003. Epub, 2017 Feb 9. PMID:28190768 doi:http://dx.doi.org/10.1016/j.molcel.2017.01.003
- ↑ Palazzo L, Leidecker O, Prokhorova E, Dauben H, Matic I, Ahel I. Serine is the major residue for ADP-ribosylation upon DNA damage. Elife. 2018 Feb 26;7. pii: 34334. doi: 10.7554/eLife.34334. PMID:29480802 doi:http://dx.doi.org/10.7554/eLife.34334
- ↑ Bartlett E, Bonfiglio JJ, Prokhorova E, Colby T, Zobel F, Ahel I, Matic I. Interplay of Histone Marks with Serine ADP-Ribosylation. Cell Rep. 2018 Sep 25;24(13):3488-3502.e5. doi: 10.1016/j.celrep.2018.08.092. PMID:30257210 doi:http://dx.doi.org/10.1016/j.celrep.2018.08.092
- ↑ Suskiewicz MJ, Zobel F, Ogden TEH, Fontana P, Ariza A, Yang JC, Zhu K, Bracken L, Hawthorne WJ, Ahel D, Neuhaus D, Ahel I. HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation. Nature. 2020 Feb 6. pii: 10.1038/s41586-020-2013-6. doi:, 10.1038/s41586-020-2013-6. PMID:32028527 doi:http://dx.doi.org/10.1038/s41586-020-2013-6
|
